1. Field of the Invention
The invention relates to a multilayered film-shaped therapeutic system for transmucosal administration of active substances, especially of medicinal substances. These systems are suitable for rapid delivery of active substances over. a prolonged period in a controlled manner.
2. Description of the Prior Art
Mucoadhesive medicament forms are known in the state of the art for example in the form of mucoadhesive tablets, disks or film-shaped administration forms. Some of those medicament forms are already available on the market. Mucoadhesive medicament forms are applied to the mucosa, especially to the oral mucosa (buccal and/or gingival mucosa), thereby enabling the delivery of the active substance contained therein and absorption via the mucosa. It is advantageous here that the active substances enter the circulation quickly and a quick onset of action can be achieved. Medicament forms of this kind are suitable, in particular, for administering such active substances that are poorly absorbed by the gastrointestinal tract and/or exhibit a short plasma half-life.
The best known mucoadhesive administration forms are tablets which are configured in two layers and consist of a mucoadhesive layer and a retarding backing layer (AFTAB®, Rottapharm). There have been endeavours to improve the functional capability of such mucoadhesive tablets, for example by providing drainage notches which enable saliva liquid to be transported away from the application site. Such tablet systems are indeed capable of fulfilling their function, but they are experienced as unpleasant to the patients since they are relatively thick, hard and inflexible, and thereby induce a marked foreign body sensation.
Apart from the above, mucoadhesive “disks” are known which can be formulated on the basis of lipophile, insoluble polymer matrices and hydrophile mucoadhesive polymers and, if required, surfactants. These disks usually have a thickness of approx. 1 mm and therefore cause an unpleasant foreign body-sensation in the mouth.
From U.S. Pat. No. 4,713,243 there are known mono- or multilayered mucoadhesive films whose mucoadhesive layer consists of hydroxypropyl cellulose, an ethylene oxide homopolymer, a water-insoluble polymer (e.g. ethyl cellulose, propyl cellulose, polyethylene, polypropylene) and a plasticizer. These administration forms are considered more pleasant by the patients, but their usefulness is highly restricted on account of the only short period of adhesion. This short duration of adhesion is due to the fact that the polymers employed are readily soluble in water, so that no appreciable retardation of adhesion does occur. To achieve that the mentioned mucoadhesive films adhere to the mucosa for a prolonged period of time, the content of water-insoluble polymer components (e.g. ethyl cellulose, propyl cellulose) in the formulation must be increased. However, as a consequence, the mucoadhesive systems thus produced have a greater thickness, which increases the foreign body sensation during the period of application. In addition, the greater thickness entails a decrease in the release of active substance since the diffusion paths become longer and the diffusion coefficients diminish.
It has also been proposed (Patent No. U.S. Pat. No. 5,719,197) to improve the coherence of mucoadhesive systems by using clay as an additive. However, such clays must be regarded as disadvantageous because of their property of adsorbing certain active substances or of affecting the active substance stability by catalytic effects. Furthermore, the weight and thickness of the system is markedly increased by these additives.
The task underlying the present invention was thereby to provide mucoadhesive administration forms which do not have the above-mentioned disadvantages, in particular inducement of a foreign body sensation, insufficient active substance release and too short a duration of adhesion.
Furthermore, these mucoadhesive medicament forms are to enable a quick onset of action on the one hand and on the other hand, enable a continuous and controlled active substance delivery over a prolonged period of time.